tbuckley/cabot-search huggingface dataset:
Cardiovascular Brain Circuits
Authors: Sarajo K. Mohanta, Changjun Yin, Christian Weber, Cristina Godinho-Silva, Henrique Veiga-Fernandes, Qian J. Xu, Rui B. Chang, Andreas J.R. Habenicht
Journal: Circulation Research (2023)

The cardiovascular system is hardwired to the brain via multilayered afferent and efferent polysynaptic axonal connections. Two major anatomically and functionally distinct though closely interacting subcircuits within the cardiovascular system have recently been defined: The artery-brain circuit and the heart-brain circuit. However, how the nervous system impacts cardiovascular disease progression remains poorly understood. Here, we review recent findings on the anatomy, structures, and inner workings of the lesser-known artery-brain circuit and the better-established heart-brain circuit. We explore the evidence that signals from arteries or the heart form a systemic and finely tuned cardiovascular brain circuit: afferent inputs originating in the arterial tree or the heart are conveyed to distinct sensory neurons in the brain. There, primary integration centers act as hubs that receive and integrate artery-brain circuit–derived and heart-brain circuit–derived signals and process them together with axonal connections and humoral cues from distant brain regions. To conclude the cardiovascular brain circuit, integration centers transmit the constantly modified signals to efferent neurons which transfer them back to the cardiovascular system. Importantly, primary integration centers are wired to and receive information from secondary brain centers that control a wide variety of brain traits encoded in engrams including immune memory, stress-regulating hormone release, pain, reward, emotions, and even motivated types of behavior. Finally, we explore the important possibility that brain effector neurons in the cardiovascular brain circuit network connect efferent signals to other peripheral organs including the immune system, the gut, the liver, and adipose tissue. The enormous recent progress vis-à-vis the cardiovascular brain circuit allows us to propose a novel neurobiology-centered cardiovascular disease hypothesis that we term the neuroimmune cardiovascular circuit hypothesis.
LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations.
Authors: James Chih-Hsin Yang, Martin H. Schuler, Nobuyuki Yamamoto, Kenneth John O'Byrne, Vera Hirsh, Tony Mok, Sarayut Lucien Geater, Sergey V Orlov, Chun-Ming Tsai, Michael J. Boyer, Wu-Chou Su, Jaafar Bennouna, Terufumi Kato, Vera Gorbunova, Ki Hyeong Lee, Riyaz N.H. Shah, Dan Massey, Robert M. Lorence, Mehdi Shahidi, Lecia V. Sequist
Journal: Journal of Clinical Oncology (2012)

LBA7500 Background: Afatinib (A) is a selective, orally bioavailable, irreversible ErbB family blocker of EGFR (ErbB1), HER2 (ErbB2), and ErbB4. This global study investigated the efficacy and safety of A compared with pemetrexed/cisplatin (PC) in pts with EGFR mutation positive advanced lung adenocarcinoma. Methods: Following central testing for EGFR mutations (companion diagnostic TheraScreen EGFR RGQ PCR kit), 345 pts (stage IIIB/IV, PS 0–1, chemo-naive) were randomized 2:1 (A: 230; PC: 115) to daily A 40 mg or iv PC (500 mg/m 2 + 75 mg/m 2 q21 days up to 6 cycles). Primary endpoint was progression-free survival (PFS) by central independent review. Results: Baseline characteristics were balanced in both arms: median age, 61 y; female, 65%; Asian, 72%; never-smoker, 68%; Del19, 49%; L858R, 40%; other mutations, 11%. Treatment with A led to a significantly prolonged PFS vs PC (median 11.1 vs 6.9 mos; HR 0.58 [0.43–0.78]; p=0.0004). In 308 pts with common mutations (Del19/L858R), median PFS was 13.6 vs 6.9 mos, respectively (HR=0.47 [0.34–0.65]; p&lt;0.0001). Objective response rate was significantly higher with A (56% vs 23%; p&lt;0.0001). Significant delay in time to deterioration of cancer-related symptoms of cough (HR=0.60, p=0.0072) and dyspnea (HR=0.68, p=0.0145) was seen with A vs PC. Most common drug-related adverse events (AEs) were diarrhea (95%), rash (62%) and paronychia (57%) with A, and nausea (66%), decreased appetite (53%) and vomiting (42%) with PC. Drug-related AEs led to discontinuation in 8% (A; 1% due to diarrhea) and 12% of pts (PC). Conclusions: LUX-Lung 3 is the largest prospective trial in EGFR mutation positive lung cancer and the first study using pemetrexed/cisplatin as a comparator. Treatment with afatinib significantly prolonged PFS compared to PC, with significant improvements in secondary endpoints. AEs with afatinib were manageable, with a low discontinuation rate. With 4.2 mos PFS improvement in the overall population and 6.7 mos in pts with common mutations, afatinib is a clinically relevant first-line treatment option.
Mature tertiary lymphoid structures are key niches of tumour-specific immune responses in pancreatic ductal adenocarcinomas
Authors: Gabriela Sarti Kinker, Glauco Akelinghton Freire Vitiello, Ariane Barros Diniz, Mariela Pires Cabral-Piccin, Pedro Henrique Barbosa Pereira, Maria Letícia Rodrigues Carvalho, Wallax Augusto Silva Ferreira, Alexandre Silva Chaves, Amanda Rondinelli, Arianne Fagotti Gusmão, Alexandre Defelicibus, Gabriel Oliveira dos Santos, Warley Abreu Nunes, Laura Carolina López Claro, Talita Magalhães Bernardo, Ricardo Tadashi Nishio, Adhemar Monteiro Pacheco, Ana Carolina Laus, Lidia Maria Rebolho Batista Arantes, Julia Lima Fleck, Victor Hugo Fonseca de Jesus, André de Moricz, Ricardo Weinlich, Felipe José Fernandez Coimbra, Vladmir Cláudio Cordeiro de Lima, Tiago da Silva Medina
Journal: Gut (2023)

To better understand the immune microenvironment of pancreatic ductal adenocarcinomas (PDACs), here we explored the relevance of T and B cell compartmentalisation into tertiary lymphoid structures (TLSs) for the generation of local antitumour immunity.We characterised the functional states and spatial organisation of PDAC-infiltrating T and B cells using single-cell RNA sequencing (scRNA-seq), flow cytometry, multicolour immunofluorescence, gene expression profiling of microdissected TLSs, as well as in vitro assays. In addition, we performed a pan-cancer analysis of tumour-infiltrating T cells using scRNA-seq and sc T cell receptor sequencing datasets from eight cancer types. To evaluate the clinical relevance of our findings, we used PDAC bulk RNA-seq data from The Cancer Genome Atlas and the PRINCE chemoimmunotherapy trial.We found that a subset of PDACs harbours fully developed TLSs where B cells proliferate and differentiate into plasma cells. These mature TLSs also support T cell activity and are enriched with tumour-reactive T cells. Importantly, we showed that chronically activated, tumour-reactive T cells exposed to fibroblast-derived TGF-β may act as TLS organisers by producing the B cell chemoattractant CXCL13. Identification of highly similar subsets of clonally expanded CXCL13+ tumour-infiltrating T cells across multiple cancer types further indicated a conserved link between tumour-antigen recognition and the allocation of B cells within sheltered hubs in the tumour microenvironment. Finally, we showed that the expression of a gene signature reflecting mature TLSs was enriched in pretreatment biopsies from PDAC patients with longer survival after receiving different chemoimmunotherapy regimens.We provided a framework for understanding the biological role of PDAC-associated TLSs and revealed their potential to guide the selection of patients for future immunotherapy trials.
Mitigating long-term and delayed adverse events associated with cancer treatment: implications for survivorship
Authors: Maryam B. Lustberg, Nicole M. Kuderer, Aakash Desai, Cristiane Bergerot, Gary H. Lyman
Journal: Nature Reviews Clinical Oncology (2023)

Despite the importance of chemotherapy-associated adverse events in oncology practice and the broad range of interventions available to mitigate them, limited systematic efforts have been made to identify, critically appraise and summarize the totality of evidence on the effectiveness of these interventions. Herein, we review the most common long-term (continued beyond treatment) and late or delayed (following treatment) adverse events associated with chemotherapy and other anticancer treatments that pose major threats in terms of survival, quality of life and continuation of optimal therapy. These adverse effects often emerge during and continue beyond the course of therapy or arise among survivors in the months and years following treatment. For each of these adverse effects, we discuss and critically evaluate their underlying biological mechanisms, the most commonly used pharmacological and non-pharmacological treatment strategies, and evidence-based clinical practice guidelines for their appropriate management. Furthermore, we discuss risk factors and validated risk-assessment tools for identifying patients most likely to be harmed by chemotherapy and potentially benefit from effective interventions. Finally, we highlight promising emerging supportive-care opportunities for the ever-increasing number of cancer survivors at continuing risk of adverse treatment effects. The effective management of treatment-related events remains an unmet need in oncology. The authors of this Review discuss the underlying biological mechanisms, risk factors, most commonly used pharmacological and non-pharmacological management strategies, and clinical practice guidelines for the most common long-term (continuing beyond treatment) and late or delayed (following treatment) adverse events associated with chemotherapy and other anticancer treatments.
Rheumatology and Long COVID: lessons from the study of fibromyalgia
Authors: Daniel J Clauw, Leonard Calabrese
Journal: Annals of the Rheumatic Diseases (2023)

Rheumatology, such as other subspecialties, has both a unique perspective to offer as well as an evolving role to play in the global COVID-19 pandemic. Our field has already contributed meaningfully to the development and repurposing of many of the immune-based therapeutics which are now standard treatments for severe forms of the disease as well as to the understanding of the epidemiology, risk factors and natural history of COVID-19 in immune-mediated inflammatory diseases. Still in evolution is our potential to contribute to burgeoning research efforts in the next phase of the pandemic: the syndrome of postacute sequelae of COVID-19 or Long COVID. While our field brings many assets to the study of Long COVID including our expertise in the investigation of chronic inflammation and autoimmunity, our Viewpoint focuses on the strong similarities between fibromyalgia (FM) and Long COVID. While one can speculate on how embracing and confident practising rheumatologists already are regarding these interrelationships, we assert that in the emerging field of Long COVID the potential lessons from the field of fibromyalgia care and research have been underappreciated and marginalised and most importantly now deserve a critical appraisal.
Country-level socioeconomic status relates geographical latitude to the onset of RA: a worldwide cross-sectional analysis in the METEOR registry
Authors: Sytske Anne Bergstra, Alexandre Sepriano, Arvind Chopra, Lai-Ling Winchow, David Vega-Morales, Karen Salomon-Escoto, Xanthe M E Matthijssen, Robert BM Landewé
Journal: Annals of the Rheumatic Diseases (2023)

Age at rheumatoid arthritis (RA) onset varies by geographical latitude. We have investigated to what extent differences in patient-specific factors and country-level socioeconomic indicators explain this variability.Patients with RA from the worldwide METEOR registry were included. Bayesian multilevel structural equation models were used to study the relationship between the absolute value of (hospital) geographical latitude and age at diagnosis (as a proxy for age at RA onset). We examined to what extent this effect is mediated by individual patient characteristics and by country-specific socioeconomic indicators and disentangled whether the observed effects occurred at the patient, hospital, or country levels.We included 37 981 patients from 93 hospitals in 17 geographically widespread countries. Mean age at diagnosis per country ranged from 39 (Iran) to 55 (Netherlands) years. Per degree increase in country latitude (between 9.9° and 55.8°), mean age at diagnosis increased by 0.23 years (95% credibility interval: 0.095 to 0.38) (reflecting >10 years difference in age at RA onset). For hospitals within a country, this latitude effect was negligible. Inclusion of patient-specific factors (eg, gender, anticitrullinated protein antibodies status) in the model augmented the main effect from 0.23 to 0.36 years. Inclusion of country-level socioeconomic indicators (eg, gross domestic product per capita) in the model almost effaced the main effect (from 0.23 to 0.051 (-0.37 to 0.38)).Patients living closer to the equator get RA at a younger age. This latitude gradient was not explained by individual patient characteristics, but rather by countries' socioeconomic status, providing a direct link between countries' level of welfare and the clinical onset of RA.
Dendritic cell therapy augments antitumor immunity triggered by CDK4/6 inhibition and immune checkpoint blockade by unleashing systemic CD4 T-cell responses
Authors: Amrendra Kumar, Vijay Ramani, Vijaya Bharti, Daniel de Lima Bellan, Nabil Saleh, Roman Uzhachenko, Chengli Shen, Carlos Arteaga, Ann Richmond, Sangeetha M Reddy, Anna Vilgelm
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are a mainstay treatment for hormone receptor-positive breast cancer. While their principal mechanism is inhibition of cancer cell proliferation, preclinical and clinical evidence suggests that CDK4/6i can also promote antitumor T-cell responses. However, this pro-immunogenic property is yet to be successfully harnessed in the clinic, as combining CDK4/6i with immune checkpoint blockade (ICB) has not shown a definitive benefit in patients. Method We performed an in-depth analysis of the changes in the tumor immune microenvironment and systemic immune modulation associated with CDK4/6i treatment in muring breast cancer models and in patients with breast cancer using high dimensional flow cytometry and RNA sequencing. Gain and loss of function in vivo experiments employing cell transfer and depletion antibody were performed to uncover immune cell populations critical for CDK4/6i-mediated stimulation of antitumor immunity. Results We found that loss of dendritic cells (DCs) within the tumor microenvironment resulting from CDK4/6 inhibition in bone marrow progenitors is a major factor limiting antitumor immunity after CDK4/6i and ICB. Consequently, restoration of DC compartment by adoptively transferring ex vivo differentiated DCs to mice treated with CDK4/6i and ICB therapy enabled robust tumor inhibition. Mechanistically, the addition of DCs promoted the induction of tumor-localized and systemic CD4 T-cell responses in mice receiving CDK4/6i-ICB-DC combination therapy, as characterized by enrichment of programmed cell death protein-1-negative T helper (Th)1 and Th2 cells with an activated phenotype. CD4 T-cell depletion abrogated the antitumor benefit of CDK4/6i-ICB-DC combination, with outgrowing tumors displaying an increased proportion of terminally exhausted CD8 T cells. Conclusions Our findings suggest that CDK4/6i-mediated DC suppression limits CD4 T-cell responses essential for the sustained activity of CD8 T cells and tumor inhibition. Furthermore, they imply that restoring DC-CD4 T-cell crosstalk via DC transfer enables effective breast cancer immunity in response to CDK4/6i and ICB treatment.
Differential regulation of IL-17A and IL-17F via STAT5 contributes to psoriatic disease
Authors: Suzanne Cole, Avneet Manghera, Lachrissa Burns, Janine Barrett, Nicole Yager, Hefin Rhys, Andrew Skelton, John Cole, Carl S. Goodyear, Meryn Griffiths, Dominique Baeten, Marta Bertolini, Stevan Shaw, Hussein Al-Mossawi, Asher Maroof
Journal: Journal of Allergy and Clinical Immunology (2023)
Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors
Authors: Clémence Demerlé, Laurent Gorvel, Marielle Mello, Sonia Pastor, Clara Degos, Ana Zarubica, Fabien Angelis, Frédéric Fiore, Jacques A Nunes, Bernard Malissen, Laurent Greillier, Geoffrey Guittard, Hervé Luche, Fabrice Barlesi, Daniel Olive
Journal: Journal for ImmunoTherapy of Cancer (2023)

Tumor necrosis factor superfamily member 14 (TNFRSF14)/herpes virus entry mediator (HVEM) is the ligand for B and T lymphocyte attenuator (BTLA) and CD160-negative immune co-signaling molecules as well as viral proteins. Its expression is dysregulated with an overexpression in tumors and a connection with tumors of adverse prognosis.We developed C57BL/6 mouse models co-expressing human (hu)BTLA and huHVEM as well as antagonistic monoclonal antibodies (mAbs) that completely prevent the interactions of HVEM with its ligands.Here, we show that the anti-HVEM18-10 mAb increases primary human αβ-T cells activity alone (CIS-activity) or in the presence of HVEM-expressing lung or colorectal cancer cells in vitro (TRANS-activity). Anti-HVEM18-10 synergizes with antiprogrammed death-ligand 1 (anti-PD-L1) mAb to activate T cells in the presence of PD-L1-positive tumors, but is sufficient to trigger T cell activation in the presence of PD-L1-negative cells. In order to better understand HVEM18-10 effects in vivo and especially disentangle its CIS and TRANS effects, we developed a knockin (KI) mouse model expressing human BTLA (huBTLA+/+) and a KI mouse model expressing both huBTLA+/+/huHVEM+/+ (double KI (DKI)). In vivo preclinical experiments performed in both mouse models showed that HVEM18-10 treatment was efficient to decrease human HVEM+ tumor growth. In the DKI model, anti-HVEM18-10 treatment induces a decrease of exhausted CD8+ T cells and regulatory T cells and an increase of effector memory CD4+ T cells within the tumor. Interestingly, mice which completely rejected tumors (±20%) did not develop tumors on rechallenge in both settings, therefore showing a marked T cell-memory phenotype effect.Altogether, our preclinical models validate anti-HVEM18-10 as a promising therapeutic antibody to use in clinics as a monotherapy or in combination with existing immunotherapies (antiprogrammed cell death protein 1/anti-PD-L1/anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4)).
Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound
Authors: Yaoheng Yang, Jinyun Yuan, Rachael L. Field, Dezhuang Ye, Zhongtao Hu, Kevin Xu, Lu Xu, Yan Gong, Yimei Yue, Alexxai V. Kravitz, Michael R. Bruchas, Jianmin Cui, Jonathan R. Brestoff, Hong Chen
Journal: Nature Metabolism (2023)

Abstract Torpor is an energy-conserving state in which animals dramatically decrease their metabolic rate and body temperature to survive harsh environmental conditions. Here, we report the noninvasive, precise and safe induction of a torpor-like hypothermic and hypometabolic state in rodents by remote transcranial ultrasound stimulation at the hypothalamus preoptic area (POA). We achieve a long-lasting (&gt;24 h) torpor-like state in mice via closed-loop feedback control of ultrasound stimulation with automated detection of body temperature. Ultrasound-induced hypothermia and hypometabolism (UIH) is triggered by activation of POA neurons, involves the dorsomedial hypothalamus as a downstream brain region and subsequent inhibition of thermogenic brown adipose tissue. Single-nucleus RNA-sequencing of POA neurons reveals TRPM2 as an ultrasound-sensitive ion channel, the knockdown of which suppresses UIH. We also demonstrate that UIH is feasible in a non-torpid animal, the rat. Our findings establish UIH as a promising technology for the noninvasive and safe induction of a torpor-like state.
Senescence-induced immune remodeling facilitates metastatic adrenal cancer in a sex-dimorphic manner
Authors: Kate M. Warde, Lorenzo J. Smith, Lihua Liu, Chris J. Stubben, Brian K. Lohman, Parker W. Willett, Julia L. Ammer, Guadalupe Castaneda-Hernandez, Sikiru O. Imodoye, Chenge Zhang, Kara D. Jones, Kimber Converso-Baran, H. Atakan Ekiz, Marc Barry, Michael R. Clay, Katja Kiseljak-Vassiliades, Thomas J. Giordano, Gary D. Hammer, Kaitlin J. Basham
Journal: Nature Aging (2023)
Integrating genetics with single-cell multiomic measurements across disease states identifies mechanisms of beta cell dysfunction in type 2 diabetes
Authors: Gaowei Wang, Joshua Chiou, Chun Zeng, Michael Miller, Ileana Matta, Jee Yun Han, Nikita Kadakia, Mei-Lin Okino, Elisha Beebe, Medhavi Mallick, Joan Camunas-Soler, Theodore dos Santos, Xiao-Qing Dai, Cara Ellis, Yan Hang, Seung K. Kim, Patrick E. MacDonald, Fouad R. Kandeel, Sebastian Preissl, Kyle J. Gaulton, Maike Sander
Journal: Nature Genetics (2023)
Gene expression in African Americans, Puerto Ricans and Mexican Americans reveals ancestry-specific patterns of genetic architecture
Authors: Linda Kachuri, Angel C. Y. Mak, Donglei Hu, Celeste Eng, Scott Huntsman, Jennifer R. Elhawary, Namrata Gupta, Stacey Gabriel, Shujie Xiao, Kevin L. Keys, Akinyemi Oni-Orisan, José R. Rodríguez-Santana, Michael A. LeNoir, Luisa N. Borrell, Noah A. Zaitlen, L. Keoki Williams, Christopher R. Gignoux, Esteban González Burchard, Elad Ziv
Journal: Nature Genetics (2023)

We explored ancestry-related differences in the genetic architecture of whole-blood gene expression using whole-genome and RNA sequencing data from 2,733 African Americans, Puerto Ricans and Mexican Americans. We found that heritability of gene expression significantly increased with greater proportions of African genetic ancestry and decreased with higher proportions of Indigenous American ancestry, reflecting the relationship between heterozygosity and genetic variance. Among heritable protein-coding genes, the prevalence of ancestry-specific expression quantitative trait loci (anc-eQTLs) was 30% in African ancestry and 8% for Indigenous American ancestry segments. Most anc-eQTLs (89%) were driven by population differences in allele frequency. Transcriptome-wide association analyses of multi-ancestry summary statistics for 28 traits identified 79% more gene-trait associations using transcriptome prediction models trained in our admixed population than models trained using data from the Genotype-Tissue Expression project. Our study highlights the importance of measuring gene expression across large and ancestrally diverse populations for enabling new discoveries and reducing disparities.